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Optimizing Chemotherapy for Advanced Ovarian Cancer

Panelists: Bradley J. Monk, MD, University of Arizona and Creighton University; Robert L. Coleman, MD, MD Anderson Cancer Center; Gottfried E. Konecny, MD, University of California, Los Angeles; Katie Moore, MD, University of Oklahoma; Matthew A. Powell, MD, Washington University in St. Louis
Published: Tuesday, Jul 25, 2017



Transcript:

Bradley J. Monk, MD:
Gottfried, regarding chemotherapy, you’re the only medical oncologist here. What’s your go-to frontline regimen in an otherwise healthy, uncomplicated ovarian cancer?

Gottfried E. Konecny, MD: That’s a great question. I think there’s not one standard of care.

Bradley J. Monk, MD: No, but you’re the expert.

Gottfried E. Konecny, MD: Due to the recent data on intraperitoneal chemotherapy with dose-dense weekly Taxol [paclitaxel], which have been disappointing in my opinion, there’s no clear benefit regarding PFS or overall survival. It is standard Taxol/carboplatin, 6 cycles.

Bradley J. Monk, MD: Weekly or every 3 weeks?

Gottfried E. Konecny, MD: Every 3 weeks. I think there is a study where bevacizumab was given, and there’s a subset of those patients who didn’t get bevacizumab and were apparently given the regimen weekly. But I do think it’s a well-tolerated large study. If relevant at all, these differences are minimal. I felt the patients getting weekly Taxol had a harder time maintaining the treatment intervals. So, I don’t think it’s a major difference, and I think we should focus on adding new biologics, looking at appropriate subtypes, rather than focusing on optimizing chemotherapy—and hopefully not create another new trial that will look at 1500 patients.

Bradley J. Monk, MD: And it’s my sarcasm, get a bigger knife—I get it. Getting a bigger knife in the operating room doesn’t help, and these minor tweaks of carboplatin/paclitaxel don’t help. But I’ll bet you that my 3 colleagues here don’t do every 3 weeks. And every 3 weeks is fine. I would never criticize it. Rob, what’s your go-to regimen?

Robert L. Coleman, MD: Every 3 weeks. Let me just say, in the patients who have bulky disease, we are doing a lot of dose-dense treatment. We can’t get bevacizumab, which would be a reasonable alternative in the frontline setting, and it’s covered in my state. So, we do a lot of that. I am sympathetic to the high rate of treatment alterations you have to make in dose-dense treatment of patients who have optimal minimal residual disease.

Bradley J. Monk, MD: Dose-dense, for our audience, is 80 mg/m2 paclitaxel without a break. And then, carboplatin’s AUC (area under the curve) dose, generally in the United States, is 6—every 3 weeks.

Robert L. Coleman, MD: That’s correct. I’m sympathetic to that, and I would say where the patients live also impacts that. On average, the patients that I see—because we have a little bit of a different patient mix—are staying for trial or they’re going home. And if they’re going home, or if they’re coming back, we can’t do it weekly, so they do it every 3 weeks. I would say there’s a decent proportion of them.

Bradley J. Monk, MD: Matt, do you use weekly or every 3 weeks?

Matthew A. Powell, MD: It’s about half and half. And in fact, it’s getting less dose-dense now as more data accumulate, and the enthusiasm for selling it as a major step forward is waning at this point.

Bradley J. Monk, MD: Katie?

Gottfried E. Konecny, MD: I’d be really interested to know, also, not just dose-dense, but intraperitoneal therapy. Whether you’re still doing it.

Matthew A. Powell, MD: I’d say the same thing. It’s over, it’s out.

Robert L. Coleman, MD: Wait a minute, you have, Katie?

Matthew A. Powell, MD: Katie will tell us the real answer.

Katie Moore, MD: It’s like you said, we didn’t do the right trial. So, I think that I agree. We both live in rural states, so patients can’t come every week, and that’s a deciding factor. I do think the data that we have from the Japanese study, and also GOG-262, show us that on high-risk patients, dose-dense is better. And we extrapolate that to the neoadjuvant setting, actually. So, we’re almost making it up. We want to chemically cytoreduce someone as much as we can, so we can get to a successful interval debulking—if that matters. Again, we’re basing this on retrospective data, but we do use those. And then, in our patients who are maximally cytoreduced, and especially on our patients with BRCA mutations, we do like to get intraperitoneal chemotherapy in. We’ve actually gone back to the GOG-172 regimen, because we think GOG-252 made too many changes. So, we’re using it a lot less.

Bradley J. Monk, MD: We’re not going to get into intraperitoneal here, but I’m just saying that you get away with it. So, GOG-172 is no longer valid because, at least I think, it didn’t have the minor advantage of dose-dense weekly. They only had arms 1 and 2 at GOG-252, and they asked 1 question: putting carboplatin in the belly or putting it in the vein, and there’s no difference.

Robert L. Coleman, MD: With bevacizumab.

Bradley J. Monk, MD: And that’s important, because bevacizumab negates the weekly paclitaxel.

Robert L. Coleman, MD: That’s your conclusion?

Bradley J. Monk, MD: That’s the GOG-262 conclusion.

Gottfried E. Konecny, MD: Based on an underpowered subset.

Bradley J. Monk, MD: If it negates the weekly, then it actually should make GOG-252 better, not make it worse.

Robert L. Coleman, MD: I’m not arguing with you. I’m just saying that has been our conclusion based on these 2 steps.

Bradley J. Monk, MD: Do you see what I’m saying though?

Robert L. Coleman, MD: Yes.

Bradley J. Monk, MD: Bevacizumab, if it is a positive—but it’s not positive—would make a positive trial negative, not a negative trial positive.

Robert L. Coleman, MD: No, no, no. The incremental benefit of bevacizumab, when all of those groups did better—and GOG-262 was a suboptimal population, it had half of the PFS of the optimal study—so, the incremental benefit of bevacizumab on the weekly regimen in both of those trials was not demonstrated. But we didn’t have the proper control arm to actually see that effect, right? Because 26 months in all 3 arms…

Bradley J. Monk, MD: You did a 1500-patient study that’s negative, and so you continue to use it?

Robert L. Coleman, MD: There’s 1 last trial out there that we’re waiting on, right? The Japanese trial that’s looking at the dose-dense regimen.

Bradley J. Monk, MD: And if that’s negative, can we stick a fork in it?

Robert L. Coleman, MD: Of course we can.

Bradley J. Monk, MD: And will it be done?

Robert L. Coleman, MD: Yes, but I do think it’s important to recognize that, because there are all of these alterations that we’re making—altering the dose and schedule, GOG-172, now you’re going back to it—all this stuff. I would say even GOG-172 had an inappropriate control arm.

Katie Moore, MD: It might not have been the control arm, but it was almost weekly: you’re giving intraperitoneal Taxol, so you have prolonged exposure to that. It’s not only that, you’re not just giving it 2 out of 3—you’re getting the second one, right? So, why do you think it’s one of the best regimens?

Gottfried E. Konecny, MD: I hear the discrepancies, but I think an important take home message is that the patients go and get second opinions. They go to one institution and hear, “You’re supposed to get dose-dense.” They come back and get Q3 weekly. In another institution, they may be proposing intraperitoneal therapy. The patient’s confused. I think you have to emphasize that there’s room for discussion, and we base our decisions on secondary endpoints, like if you’re rural or not.

Matthew A. Powell, MD: I think Katie’s worried about that BRCA patient. There still may be a role for intraperitoneal therapy, whether or not that helps spare their bone marrow for later—whatever the factors are that are associated with it.

Gottfried E. Konecny, MD: Those are the exceptions, yes.

Katie Moore, MD: And the SOLO-1 trial may change all that, if that’s positive.

Bradley J. Monk, MD: At this meeting, speaking of intraperitoneal therapy, we have the opportunity to give heated intraperitoneal chemotherapy, called HIPEC, at the time of the operation and at the time of interval debulking. There’s a randomized trial from the Netherlands to show that HIPEC interval debulking showed an overall survival advantage. So, can you do that now?

Matthew A. Powell, MD: Well, it wasn’t a subtle finding. The hazard ratio was 0.65—48 versus 34 months. It’s almost too good, as we say. It’s suspicious. What’s going on? Why is it such a good finding?

Bradley J. Monk, MD: Why do we do clinical trials if we give intraperitoneal therapy when it’s negative? And then, when it’s positive, you don’t do it?

Katie Moore, MD: Well, it’s a randomized phase II trial.

Bradley J. Monk, MD: Phase III.

Robert L. Coleman, MD: Randomized phase III—245 patients were randomized.

Bradley J. Monk, MD: It’s a small sample.

Katie Moore, MD: It’s a very small sample size.

Robert L. Coleman, MD: It is what it is.

Matthew A. Powell, MD: And the patients had to meet certain criteria. They had to have very small volume disease at the time of interval cytoreduction and had to have less than 2.5-mm implants at the end of that cytoreduction to get randomized to HIPEC versus observation. But there are pretty staggering differences in survival. They also used 100 mg/m2 of cisplatin.

Gottfried E. Konecny, MD: Patients got 3 preoperative cycles of HIPEC therapy, then 3 postoperative cycles. So, they actually got more chemotherapy. They got 100 mg/m2 of cisplatin as intraperitoneal therapy. That’s a high dose of cisplatin in the intraperitoneal setting.

Matthew A. Powell, MD: But the toxicity was reassuring.

Bradley J. Monk, MD: It takes 2 trials to convince anyone of anything. And for the dose-dense, we have the Japanese trial. But we don’t have a confirmatory trial.

Matthew A. Powell, MD: Right.

Bradley J. Monk, MD: You talked about GOG-252 intraperitoneal while you wait for the Japanese trial. So, I think this is what it is. But once we have a second trial in this interval—cytoreductions, HIPEC—then I’d be concerned.

Matthew A. Powell, MD: You mentioned a second trial. The Koreans also had a study presented at the 2017 ASCO Annual Meeting.

Bradley J. Monk, MD: It was frontline HIPEC.

Matthew A. Powell, MD: But they had a subset that had neoadjuvant as well, and that was the group that actually showed some preliminarily benefit.

Bradley J. Monk, MD: GOG-262 doesn’t count as the supporting trial for the dose-dense weekly Japanese trial. It’s true, the subset suggests it. And in frontline HIPEC, the interval patients who got HIPEC also suggest it, so it’s close.

Gottfried E. Konecny, MD: But this demonstrated that if you’re platinum-sensitive, like in the Dutch study, that you have stabilization—no progressive disease. That is a subgroup of patients, or it is actually the majority, who may benefit from additional treatment.

Robert L. Coleman, MD: And I think that this is not an unheard-of concept that’s being practiced, already, in the clinic. Some people are already doing this—neoadjuvant surgery, and then they give intraperitoneal—because they had an optimal outcome that they wouldn’t have given before. But I think that both of these are cases where the publication is really important, because a lot of the questions we’re raising are things that would come out in the peer process. I think that’s where we’re going to need to really dig into it.

Transcript Edited for Clarity

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Transcript:

Bradley J. Monk, MD:
Gottfried, regarding chemotherapy, you’re the only medical oncologist here. What’s your go-to frontline regimen in an otherwise healthy, uncomplicated ovarian cancer?

Gottfried E. Konecny, MD: That’s a great question. I think there’s not one standard of care.

Bradley J. Monk, MD: No, but you’re the expert.

Gottfried E. Konecny, MD: Due to the recent data on intraperitoneal chemotherapy with dose-dense weekly Taxol [paclitaxel], which have been disappointing in my opinion, there’s no clear benefit regarding PFS or overall survival. It is standard Taxol/carboplatin, 6 cycles.

Bradley J. Monk, MD: Weekly or every 3 weeks?

Gottfried E. Konecny, MD: Every 3 weeks. I think there is a study where bevacizumab was given, and there’s a subset of those patients who didn’t get bevacizumab and were apparently given the regimen weekly. But I do think it’s a well-tolerated large study. If relevant at all, these differences are minimal. I felt the patients getting weekly Taxol had a harder time maintaining the treatment intervals. So, I don’t think it’s a major difference, and I think we should focus on adding new biologics, looking at appropriate subtypes, rather than focusing on optimizing chemotherapy—and hopefully not create another new trial that will look at 1500 patients.

Bradley J. Monk, MD: And it’s my sarcasm, get a bigger knife—I get it. Getting a bigger knife in the operating room doesn’t help, and these minor tweaks of carboplatin/paclitaxel don’t help. But I’ll bet you that my 3 colleagues here don’t do every 3 weeks. And every 3 weeks is fine. I would never criticize it. Rob, what’s your go-to regimen?

Robert L. Coleman, MD: Every 3 weeks. Let me just say, in the patients who have bulky disease, we are doing a lot of dose-dense treatment. We can’t get bevacizumab, which would be a reasonable alternative in the frontline setting, and it’s covered in my state. So, we do a lot of that. I am sympathetic to the high rate of treatment alterations you have to make in dose-dense treatment of patients who have optimal minimal residual disease.

Bradley J. Monk, MD: Dose-dense, for our audience, is 80 mg/m2 paclitaxel without a break. And then, carboplatin’s AUC (area under the curve) dose, generally in the United States, is 6—every 3 weeks.

Robert L. Coleman, MD: That’s correct. I’m sympathetic to that, and I would say where the patients live also impacts that. On average, the patients that I see—because we have a little bit of a different patient mix—are staying for trial or they’re going home. And if they’re going home, or if they’re coming back, we can’t do it weekly, so they do it every 3 weeks. I would say there’s a decent proportion of them.

Bradley J. Monk, MD: Matt, do you use weekly or every 3 weeks?

Matthew A. Powell, MD: It’s about half and half. And in fact, it’s getting less dose-dense now as more data accumulate, and the enthusiasm for selling it as a major step forward is waning at this point.

Bradley J. Monk, MD: Katie?

Gottfried E. Konecny, MD: I’d be really interested to know, also, not just dose-dense, but intraperitoneal therapy. Whether you’re still doing it.

Matthew A. Powell, MD: I’d say the same thing. It’s over, it’s out.

Robert L. Coleman, MD: Wait a minute, you have, Katie?

Matthew A. Powell, MD: Katie will tell us the real answer.

Katie Moore, MD: It’s like you said, we didn’t do the right trial. So, I think that I agree. We both live in rural states, so patients can’t come every week, and that’s a deciding factor. I do think the data that we have from the Japanese study, and also GOG-262, show us that on high-risk patients, dose-dense is better. And we extrapolate that to the neoadjuvant setting, actually. So, we’re almost making it up. We want to chemically cytoreduce someone as much as we can, so we can get to a successful interval debulking—if that matters. Again, we’re basing this on retrospective data, but we do use those. And then, in our patients who are maximally cytoreduced, and especially on our patients with BRCA mutations, we do like to get intraperitoneal chemotherapy in. We’ve actually gone back to the GOG-172 regimen, because we think GOG-252 made too many changes. So, we’re using it a lot less.

Bradley J. Monk, MD: We’re not going to get into intraperitoneal here, but I’m just saying that you get away with it. So, GOG-172 is no longer valid because, at least I think, it didn’t have the minor advantage of dose-dense weekly. They only had arms 1 and 2 at GOG-252, and they asked 1 question: putting carboplatin in the belly or putting it in the vein, and there’s no difference.

Robert L. Coleman, MD: With bevacizumab.

Bradley J. Monk, MD: And that’s important, because bevacizumab negates the weekly paclitaxel.

Robert L. Coleman, MD: That’s your conclusion?

Bradley J. Monk, MD: That’s the GOG-262 conclusion.

Gottfried E. Konecny, MD: Based on an underpowered subset.

Bradley J. Monk, MD: If it negates the weekly, then it actually should make GOG-252 better, not make it worse.

Robert L. Coleman, MD: I’m not arguing with you. I’m just saying that has been our conclusion based on these 2 steps.

Bradley J. Monk, MD: Do you see what I’m saying though?

Robert L. Coleman, MD: Yes.

Bradley J. Monk, MD: Bevacizumab, if it is a positive—but it’s not positive—would make a positive trial negative, not a negative trial positive.

Robert L. Coleman, MD: No, no, no. The incremental benefit of bevacizumab, when all of those groups did better—and GOG-262 was a suboptimal population, it had half of the PFS of the optimal study—so, the incremental benefit of bevacizumab on the weekly regimen in both of those trials was not demonstrated. But we didn’t have the proper control arm to actually see that effect, right? Because 26 months in all 3 arms…

Bradley J. Monk, MD: You did a 1500-patient study that’s negative, and so you continue to use it?

Robert L. Coleman, MD: There’s 1 last trial out there that we’re waiting on, right? The Japanese trial that’s looking at the dose-dense regimen.

Bradley J. Monk, MD: And if that’s negative, can we stick a fork in it?

Robert L. Coleman, MD: Of course we can.

Bradley J. Monk, MD: And will it be done?

Robert L. Coleman, MD: Yes, but I do think it’s important to recognize that, because there are all of these alterations that we’re making—altering the dose and schedule, GOG-172, now you’re going back to it—all this stuff. I would say even GOG-172 had an inappropriate control arm.

Katie Moore, MD: It might not have been the control arm, but it was almost weekly: you’re giving intraperitoneal Taxol, so you have prolonged exposure to that. It’s not only that, you’re not just giving it 2 out of 3—you’re getting the second one, right? So, why do you think it’s one of the best regimens?

Gottfried E. Konecny, MD: I hear the discrepancies, but I think an important take home message is that the patients go and get second opinions. They go to one institution and hear, “You’re supposed to get dose-dense.” They come back and get Q3 weekly. In another institution, they may be proposing intraperitoneal therapy. The patient’s confused. I think you have to emphasize that there’s room for discussion, and we base our decisions on secondary endpoints, like if you’re rural or not.

Matthew A. Powell, MD: I think Katie’s worried about that BRCA patient. There still may be a role for intraperitoneal therapy, whether or not that helps spare their bone marrow for later—whatever the factors are that are associated with it.

Gottfried E. Konecny, MD: Those are the exceptions, yes.

Katie Moore, MD: And the SOLO-1 trial may change all that, if that’s positive.

Bradley J. Monk, MD: At this meeting, speaking of intraperitoneal therapy, we have the opportunity to give heated intraperitoneal chemotherapy, called HIPEC, at the time of the operation and at the time of interval debulking. There’s a randomized trial from the Netherlands to show that HIPEC interval debulking showed an overall survival advantage. So, can you do that now?

Matthew A. Powell, MD: Well, it wasn’t a subtle finding. The hazard ratio was 0.65—48 versus 34 months. It’s almost too good, as we say. It’s suspicious. What’s going on? Why is it such a good finding?

Bradley J. Monk, MD: Why do we do clinical trials if we give intraperitoneal therapy when it’s negative? And then, when it’s positive, you don’t do it?

Katie Moore, MD: Well, it’s a randomized phase II trial.

Bradley J. Monk, MD: Phase III.

Robert L. Coleman, MD: Randomized phase III—245 patients were randomized.

Bradley J. Monk, MD: It’s a small sample.

Katie Moore, MD: It’s a very small sample size.

Robert L. Coleman, MD: It is what it is.

Matthew A. Powell, MD: And the patients had to meet certain criteria. They had to have very small volume disease at the time of interval cytoreduction and had to have less than 2.5-mm implants at the end of that cytoreduction to get randomized to HIPEC versus observation. But there are pretty staggering differences in survival. They also used 100 mg/m2 of cisplatin.

Gottfried E. Konecny, MD: Patients got 3 preoperative cycles of HIPEC therapy, then 3 postoperative cycles. So, they actually got more chemotherapy. They got 100 mg/m2 of cisplatin as intraperitoneal therapy. That’s a high dose of cisplatin in the intraperitoneal setting.

Matthew A. Powell, MD: But the toxicity was reassuring.

Bradley J. Monk, MD: It takes 2 trials to convince anyone of anything. And for the dose-dense, we have the Japanese trial. But we don’t have a confirmatory trial.

Matthew A. Powell, MD: Right.

Bradley J. Monk, MD: You talked about GOG-252 intraperitoneal while you wait for the Japanese trial. So, I think this is what it is. But once we have a second trial in this interval—cytoreductions, HIPEC—then I’d be concerned.

Matthew A. Powell, MD: You mentioned a second trial. The Koreans also had a study presented at the 2017 ASCO Annual Meeting.

Bradley J. Monk, MD: It was frontline HIPEC.

Matthew A. Powell, MD: But they had a subset that had neoadjuvant as well, and that was the group that actually showed some preliminarily benefit.

Bradley J. Monk, MD: GOG-262 doesn’t count as the supporting trial for the dose-dense weekly Japanese trial. It’s true, the subset suggests it. And in frontline HIPEC, the interval patients who got HIPEC also suggest it, so it’s close.

Gottfried E. Konecny, MD: But this demonstrated that if you’re platinum-sensitive, like in the Dutch study, that you have stabilization—no progressive disease. That is a subgroup of patients, or it is actually the majority, who may benefit from additional treatment.

Robert L. Coleman, MD: And I think that this is not an unheard-of concept that’s being practiced, already, in the clinic. Some people are already doing this—neoadjuvant surgery, and then they give intraperitoneal—because they had an optimal outcome that they wouldn’t have given before. But I think that both of these are cases where the publication is really important, because a lot of the questions we’re raising are things that would come out in the peer process. I think that’s where we’re going to need to really dig into it.

Transcript Edited for Clarity
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